New forms of dementia in neurodegenerative diseases: molecular basis, phenomenology, and diagnostic capability

In the light of the development of molecular biology and pathomorphology, ideas about degenerative diseases of the nervous system are gradually changing. A clear evidence of this is the description in recent years of new forms of neurodegenerative pathology, manifested by cognitive decline and dementia. These forms include Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE); dementia associated with Quadruple Misfolded Proteins (QMP), Neuronal Intranuclear Inclusion Disease (NIID). Their appearance in a wide range of neurodegenerative diseases, characterized at the molecular and phenotypic level, raises several questions — from the introduction of new complex terms into the Russian-language scientific literature to the formation of new knowledge among specialists to identify these conditions in practice. The review examines in detail the spectrum of clinical manifestations and genetic characteristics of new forms of neurodegenerative dementia, as well as modern possibilities of their diagnosis.

1. Yakhno N.N., Zaharov V.V., Lokshina A.B., Koberskaja N.N., Mhitarjan Je.A. Demencii. Rukovodstvo dlja vrachej. Moskva: MEDpress-inform, 2010:272 p. (In Russ.)

2. van der Flier W.M., Scheltens P. Epidemiology and risk factors of dementia. Journal of Neurology, Neurosurgery & Psychiatry. 2005;76(suppl.5):v2–7. http://dx.doi.org/10.1136/jnnp.2005.082867

3. James B.D., Wilson R.S., Boyle P.A., Trojanowski J.Q., Bennett D.A., Schneider J.A. TDP-43 stage, mixed pathologies, and clinical Alzheimer’s-type dementia. Brain. 2016;139(11):2983–2993. https://doi.org/10.1093/brain/aww224

4. Brenowitz W.D., Monsell S.E., Schmitt F.A., Kukull W.A., Nelson P.T. Hippocampal sclerosis of aging is a key Alzheimer’s disease mimic: clinical-pathologic correlations and comparisons with both Alzheimer’s disease and non-tauopathic frontotemporal lobar degeneration. Journal of Alzheimer’s Disease. 2014;39(3):691–702. doi: 10.3233/JAD-131880

5. Pao W.C., Dickson D.W., Crook J.E., Finch N.A., Rademakers R., Graff-Radford N.R. Hippocampal sclerosis in the elderly: genetic and pathologic fi ndings, some mimicking Alzheimer disease clinically. Alzheimer disease and associated disorders. 2011;25(4): 364–368. doi: 10.1097/WAD.0b013e31820f8f50

6. Nelson P.T., Dickson D.W., Trojanowski J.Q., Jack C.R., Boyle P.A., Arfanakis K., Rademakers R., Alafuzoff I., Attems J., Brayne C., Coyle-Gilchrist I.T. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain. 2019;142(6): 1503–1527. https://doi.org/10.1093/brain/awz099

7. Robinson J.L., Lee E.B., Xie S.X., Rennert L., Suh E., Bredenberg C., Caswell C., Van Deerlin V.M., Yan N., Yousef A., Hurtig H.I. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain. 2018;141(7): 2181–2193. https://doi.org/10.1093/brain/awy146

8. Karanth S., Nelson P.T., Katsumata Y., Kryscio R.J., Schmitt F.A., Fardo D.W., Cykowski M.D., Jicha G.A., Van Eldik L.J., Abner E.L. Prevalence and clinical phenotype of quadruple misfolded proteins in older adults. JAMA Neurology. 2020;77(10): 1299–1307. doi:10.1001/jamaneurol.2020.1741

9. Lindenberg R., Rubinstein L.J., Herman M.M., Haydon G.B. A light and electron microscopy study of an unusual widespread nuclear inclusion body disease. Acta neuropathologica. 1968;10(1): 54–73. https://link.springer.com/content/pdf/10.1007/BF00690510.pdf (на момент 30 июня 2021 года).

10. Sone J., Mori K., Inagaki T., Katsumata R., Takagi S., Yokoi S., Araki K., Kato T., Nakamura T., Koike H., Takashima H. Clinicopathological features of adult-onset neuronal intranuclear inclusion disease. Brain. 2016;139(12): 3170–3186. https://doi.org/10.1093/brain/aww249

11. Ishiura H., Shibata S., Yoshimura J., Suzuki Y., Qu W., Doi K., Almansour M.A., Kikuchi J.K., Taira M., Mitsui J., Takahashi Y. Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Nature genetics. 2019;51(8): 1222–1232. https://doi.org/10.1038/s41588-019-0458-z

12. Sone J., Mitsuhashi S., Fujita A., Mizuguchi T., Hamanaka K., Mori K., Koike H., Hashiguchi A., Takashima H., Sugiyama H., Kohno Y. Long-read sequencing identifi es GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease. Nature genetics. 2019;51(8): 1215–1221. https://doi.org/10.1038/s41588-019-0459-y

13. Tian Y., Wang J.L., Huang W., Zeng S., Jiao B., Liu Z., Chen Z., Li Y., Wang Y., Min H.X., Wang X.J. Expansion of human-specifi c GGC repeat in neuronal intranuclear inclusion disease-related disorders. The American Journal of Human Genetics. 2019;105(1): 166–176. https://doi.org/10.1016/j.ajhg.2019.05.013

14. Callister J.B., Pickering-Brown S.M. Pathogenesis/genetics of frontotemporal dementia and how it relates to ALS. Experimental neurology. 2014;262:84–90. https://doi.org/10.1016/j.expneurol.2014.06.001

15. Guo L., Shorter J. Biology and pathobiology of TDP-43 and emergent therapeutic strategies. Cold Spring Harbor Perspectives in Medicine. 2017;7(9):a024554. doi: 10.1101/cshperspect.a024554

16. Neumann M., Sampathu D.M., Kwong L.K., Truax A.C., Micsenyi M.C., Chou T.T., Bruce J., Schuck T., Grossman M., Clark C.M., McCluskey L.F. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796): 130–133. doi: 10.1126/science.1134108

17. Woo J.A., Liu T., Trotter C., Fang C.C., De Narvaez E., Le Pochat P., Maslar D., Bukhari A., Zhao X., Deonarine A., Westerheide S.D. Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity. Nature communications. 2017;8(1):1–5. https://doi.org/10.1038/ncomms15558

18. Polymenidou M., Lagier-Tourenne C., Hutt K.R., Huelga S.C., Moran J., Liang T.Y., Ling S.C., Sun E., Wancewicz E., Mazur C., Kordasiewicz H. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nature neuroscience. 2011;14(4):459–468. https://doi.org/10.1038/nn.2779

19. Huang C.C., Bose J.K., Majumder P., Lee K.H., Huang J.T., Huang J.K., Shen C.K. Metabolism and mis-metabolism of the neuropathological signature protein TDP-43. Journal of Cell Science. 2014;127(14):3024–3038. https://doi.org/10.1242/jcs.136150

20. Dickson D.W., Davies P., Bevona C., Van Hoeven K.H., Factor S.M., Grober E., Aronson M.K., Crystal H.A. Hippocampal sclerosis: a common pathological feature of dementia in very old (≥ 80 years of age) humans. Acta Neuropathologica. 1994;88(3): 212–221. https://link.springer.com/content/pdf/10.1007/BF00293396.pdf (на момент 30 июня 2021 года)

21. Amador-Ortiz C., Lin W.L., Ahmed Z., Personett D., Davies P., Duara R., Graff-Radford N.R., Hutton M.L., Dickson D.W. TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 2007;61(5): 435–445. https://doi.org/10.1002/ana.21154

22. Nag S., Yu L., Wilson R.S., Chen E.Y., Bennett D.A., Schneider J.A. TDP-43 pathology and memory impairment in elders without pathologic diagnoses of AD or FTLD. Neurology. 2017;88(7): 653–660. https://doi.org/10.1212/WNL.0000000000003610

23. Kero M., Raunio A., Polvikoski T., Tienari P.J., Paetau A., Myllykangas L. Hippocampal sclerosis in the oldest old: a Finnish population-based study. Journal of Alzheimer’s Disease. 2018;63(1):263–272. doi: 10.3233/JAD-171068

24. Irwin D.J., McMillan C.T., Xie S.X., Rascovsky K., Van Deerlin V.M., Coslett H.B., Hamilton R., Aguirre G.K., Lee E.B., Lee V.M., Trojanowski J.Q. Asymmetry of postmortem neuropathology in behavioural-variant frontotemporal dementia. Brain. 2018;141(1): 288–301. https://doi.org/10.1093/brain/awx319

25. Nelson P.T., Estus S., Abner E.L., Parikh I., Malik M., Neltner J.H., Ighodaro E., Wang W.X., Wilfred B.R., Wang L.S., Kukull W.A. ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology. Acta Neuropathol. 2014;127)6): 825–843. doi: 10.1007/s00401-014-1282-2

26. Shpilyukova Yu.A., Fedotova E.Yu., Illarioshkin S.N. Genetic Diversity in Frontotemporal Dementia. Molecular Biology. 2020;54(1): 13–23. (In Russ.) doi: 10.1134/S0026893320010136

27. Barancevich E.R., Koval’chuk Yu.P., Mel’nikova E.V., Emanuel’ V.S., Emanuel’ Yu.V. Difficulties of clinical diagnosis in primary progressive aphasia. Clinical observation. Annals of clinical and experimental neurology. 2019;13(1):78–83. (In Russ.) doi: 10.25692/ACEN.2019.1.9

28. Boyle P.A., Yang J., Yu.L., Leurgans S.E., Capuano A.W., Schneider J.A., Wilson R.S., Bennett D.A. Varied effects of agerelated neuropathologies on the trajectory of late life cognitive decline. Brain. 2017;140(3):804–812. https://doi.org/10.1093/brain/aww341

29. Besser L.M., Teylan M.A., Nelson P.T. Limbic predominant age-related TDP-43 encephalopathy (LATE): clinical and neuropathological associations. Journal of Neuropathology & Experimental Neurology. 2020;79(3): 305–313. https://doi.org/10.1093/jnen/nlz126

30. Pelletier A., Bernard C., Dilharreguy B., Helmer C., Le Goff M., Chanraud S., Dartigues J.F., Allard M., Amieva H., Catheline G. Patterns of brain atrophy associated with episodic memory and semantic fl uency decline in aging. Aging (Albany NY). 2017;9(3): 741–752. doi: 10.18632/aging.101186

31. Barkhof F., Polvikoski T.M., Van Straaten E.C., Kalaria R.N., Sulkava R., Aronen H.J., Niinistö L., Rastas S., Oinas M., Scheltens P., Erkinjuntti T. The signifi cance of medial temporal lobe atrophy: a postmortem MRI study in the very old. Neurology. 2007;69(15): 1521–1527. https://doi.org/10.1212/01.wnl.0000277459.83543.99

32. Zarow C., Wang L., Chui H.C., Weiner M.W., Csernansky J.G. MRI shows more severe hippocampal atrophy and shape deformation in hippocampal sclerosis than in Alzheimer’s disease. International Journal of Alzheimer’s Disease. 2011;Article ID 483972:6 p. https://doi.org/10.4061/2011/483972

33. Jack C.R., Bennett D.A., Blennow K., Carrillo M.C., Feldman H.H., Frisoni G.B., Hampel H., Jagust W.J., Johnson K.A., Knopman D.S., Petersen R.C. A/T/N: an unbiased descriptive classifi cation scheme for Alzheimer disease biomarkers. Neurology. 2016;87(5): 539–547. https://doi.org/10.1212/WNL.0000000000002923

34. Nelson P.T., Alafuzoff I., Bigio E.H., Bouras C., Braak H., Cairns N.J., Castellani R.J., Crain B.J., Davies P., Tredici K.D., Duyckaerts C. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. Journal of Neuropathology & Experimental Neurology. 2012;71(5): 362–381. https://doi.org/10.1097/NEN.0b013e31825018f7

35. Nelson P.T., Kryscio R.J., Jicha G.A., Abner E.L., Schmitt F.A., Xu L.O., Cooper G., Smith C.D., Markesbery W.R. Relative preservation of MMSE scores in autopsy-proven dementia with Lewy bodies. Neurology. 2009;73(14): 1127–1133. https://doi.org/10.1212/WNL.0b013e3181bacf9e

36. Takahashi-Fujigasaki J. Neuronal intranuclear hyaline inclusion disease. Neuropathology. 2003;23(4): 351–359. https://doi.org/10.1046/j.1440-1789.2003.00524.x

37. Fang P., Yu Y., Yao S., Chen S., Zhu M., Chen Y., Zou K., Wang L., Wang H., Xin L., Hong T. Repeat expansion scanning of the NOTCH2NLC gene in patients with multiple system atrophy. Annals of clinical and translational neurology. 2020;7(4): 517–526. https://doi.org/10.1002/acn3.51021

38. Sun Q.Y., Xu Q., Tian Y., Hu Z.M., Qin L.X., Yang J.X., Huang W., Xue J., Li J.C., Zeng S., Wang Y. Expansion of GGC repeat in the human-specifi c NOTCH2NLC gene is associated with essential tremor. Brain. 2020;143(1): 222–233. https://doi.org/10.1093/brain/awz372

39. Ma D., Tan Y.J., Ng A.S., Ong H.L., Sim W., Lim W.K., Teo J.X., Ng E.Y., Lim E.C., Lim E.W., Chan L.L. Association of NOTCH2NLC repeat expansions with Parkinson disease. JAMA Neurology. 2020;77(12): 1559–1563. doi: 10.1001/jamaneurol.2020.3023